Comprehensive Physiology Wiley Online Library

Muscle as a Secretory Organ

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Abstract

Skeletal muscle is the largest organ in the body. Skeletal muscles are primarily characterized by their mechanical activity required for posture, movement, and breathing, which depends on muscle fiber contractions. However, skeletal muscle is not just a component in our locomotor system. Recent evidence has identified skeletal muscle as a secretory organ. We have suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert either autocrine, paracrine, or endocrine effects should be classified as “myokines.” The muscle secretome consists of several hundred secreted peptides. This finding provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs such as adipose tissue, liver, pancreas, bones, and brain. In addition, several myokines exert their effects within the muscle itself. Many proteins produced by skeletal muscle are dependent upon contraction. Therefore, it is likely that myokines may contribute in the mediation of the health benefits of exercise. © 2013 American Physiological Society. Compr Physiol 3:1337‐1362, 2013.

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Figure 1. Figure 1.

Skeletal muscle is a secretory organ. Leukemia inhibitory factor (LIF), interleukin (IL)‐4, IL‐6, IL‐7, and IL‐15 promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy and exercise provokes the release of a myostatin inhibitor, follistatin, from the liver. Brain‐derived neurotropic factor (BDNF) and IL‐6 are involved in AMP‐activated protein kinase (AMPK)‐mediated fat oxidation and IL‐6 enhances insulin‐stimulated glucose uptake. IL‐6 appears to have systemic effects on the liver and adipose tissue and increases insulin secretion via upregulation of GLP‐1. Insulin‐like growth factor‐1 (IGF‐1) and FGF‐2 are involved in bone formation, and follistatin‐related protein 1 improves endothelial function and revascularization of ischemic vessels. Irisin has a role in “browning” of white adipose tissue. Adapted, with permission, from ().

Figure 2. Figure 2.

The interplay between adipokines and myokines represents a Yin‐Yang balance. Especially under conditions of obesity, adipose tissue secretes adipokines that contribute to establish a chronic inflammatory environment, promoting pathological processes such as atherosclerosis and insulin resistance. Skeletal muscles are capable of producing myokines that confer some of the health benefits of exercise. Such myokines might counteract the harmful effects of proinflammatory adipokines. Adapted, with permission, from ().

Figure 3. Figure 3.

Comparison of sepsis‐induced verses exercise‐induced increases in circulating cytokines. During sepsis, there is a marked and rapid increase in circulating tumor necrosis factor‐alpha (TNF‐α), which is followed by an increase in interleukin‐6 (IL‐6). In contrast, during exercise, the marked increase in IL‐6 is not preceded by elevated TNF‐α. Adapted, with permission, from ().

Figure 4. Figure 4.

Different modes of exercise and the corresponding increase in plasma interleukin‐6 (IL‐6) levels. Graph is based on 73 exercise trials and represents ∼800 subjects. Each dot indicates one exercise trial; the corresponding bars represent geometric means with 95% confidence intervals. Although different modes of exercise are associated with different levels of muscle damage, the increase in plasma IL‐6 levels postexercise is a consistent finding. Modified, with permission, from ().

Figure 5. Figure 5.

The overall log10‐log10 linear relation (straight solid line) between exercise duration and increase in plasma interleukin‐6 (IL‐6) (fold change from preexercise level) indicates that 51% of the variation in fold plasma IL‐6 increase may be explained by the duration of exercise. Modified, with permission, from ().

Figure 6. Figure 6.

The figure presents a model on how interleukin‐6 (IL‐6) is regulated in response to training adaptation. Regular exercise leads to an enhancement of glycogen synthase and a trained muscle will consequently store more muscle glycogen. During acute exercise, the untrained muscle is highly dependent on glycogen as substrate, whereas training leads to an enhancement of beta‐oxidating enzymes and an enhanced capability to oxidize fat and hence to use fat as substrate during exercise. This means that the trained muscle uses less glycogen during work. The activation of muscle‐IL‐6 is glycogen dependent. At conditions with low muscle glycogen, the transcription rate of IL‐6 is faster and relatively more IL‐6 is produced at the same relative work compared to conditions with high muscle glycogen. Thus, the acute plasma IL‐6 response is lower in a trained versus an untrained subject. The mechanisms whereby basal plasma‐IL‐6 is decreased by training and whereby the muscular expression of IL‐6 receptors (IL‐6R) is enhanced are not fully understood. However, it appears that a trained muscle may be more sensitive to IL‐6. Adapted, with permission, from ().

Figure 7. Figure 7.

Biological role of contraction‐induced interleukin‐6 (IL‐6). Skeletal muscle expresses and releases myokines into the circulation. In response to muscle contractions, both type I and type II muscle fibers express the myokine IL‐6, which subsequently exerts its effects both locally within the muscle (e.g., through activation of AMPK) and—when released into the circulation—peripherally in several organs in a hormone‐like fashion. Specifically in skeletal muscle, IL‐6 acts in an autocrine or paracrine manner to signal through a gp130Rβ/IL‐6Rα homodimer resulting in activation of AMP‐kinase and/or PI3‐kinase to increase glucose uptake and fat oxidation. IL‐6 is also known to increase hepatic glucose production during exercise or lipolysis in adipose tissue. Modified, with permission, from ().

Figure 8. Figure 8.

Exercise increases the intramuscular expression of peroxisome proliferator activated receptor γ coactivator 1α (PGC‐1α). Boström and colleagues recently reported that PGC‐1α, a transcriptional coactivator, stimulates the expression of the membrane protein fibronectin type III domain containing 5 (FNDC5), which is proteolytically cleaved to form irisin, a myokine. Irisin drives the transformation of white fat cells into brite cells—white fat cells with a phenotype similar to that of brown fat cells, as indicated by a marked increase in the expression of uncoupling protein 1 (UCP1) in white adipose tissue. The investigators also showed that an elevated level of plasma irisin, achieved through gene replacement, is followed by a reduction in body weight and an improvement in metabolic homeostasis in obese mice. Adapted, with permission, from ().

Figure 9. Figure 9.

Type 2 diabetes, cardiovascular diseases, colon cancer, postmenopausal breast cancer, dementia, and depression constitute a cluster of diseases, which can be identified as “the diseasome of physical inactivity”. Adapted, with permission, from ().

Figure 10. Figure 10.

Hypothesis: physical inactivity leads to accumulation of visceral fat and consequently to the activation of a network of inflammatory pathways, which promotes development of insulin resistance, atherosclerosis, neurodegeneration, and tumor growth, leading to the development of “the diseasome of physical inactivity.” Adapted, with permission, from ().

Figure 11. Figure 11.

MR‐scanning demonstrating visceral fat mass before and after 14 days of reduced daily stepping as described in ().

Figure 12. Figure 12.

The proposed cytokine signaling pathways for macrophages and contracting skeletal muscle. While it is well known that transcription of interleukin‐6 (IL‐6) and other proinflammatory cytokines such as tumor necrosis factor‐alpha (TNF‐α) and IL‐β is principally regulated by the Toll like receptor (##TLR) receptor signaling cascade that results in nuclear translocation and activation of NFκB, evidence in contracting skeletal muscle suggests that contraction leads to increased cytosolic Ca2+ and activation of p38 MAPK and/or calcineurin, which leads to activation of transcription factors depending upon these upstream events. Adapted, with permission, from ().

Figure 13. Figure 13.

The finding that muscle produces and releases myokines provides a conceptual basis for understanding some of the molecular mechanisms that link physical activity to protection against premature mortality ().



Figure 1.

Skeletal muscle is a secretory organ. Leukemia inhibitory factor (LIF), interleukin (IL)‐4, IL‐6, IL‐7, and IL‐15 promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy and exercise provokes the release of a myostatin inhibitor, follistatin, from the liver. Brain‐derived neurotropic factor (BDNF) and IL‐6 are involved in AMP‐activated protein kinase (AMPK)‐mediated fat oxidation and IL‐6 enhances insulin‐stimulated glucose uptake. IL‐6 appears to have systemic effects on the liver and adipose tissue and increases insulin secretion via upregulation of GLP‐1. Insulin‐like growth factor‐1 (IGF‐1) and FGF‐2 are involved in bone formation, and follistatin‐related protein 1 improves endothelial function and revascularization of ischemic vessels. Irisin has a role in “browning” of white adipose tissue. Adapted, with permission, from ().



Figure 2.

The interplay between adipokines and myokines represents a Yin‐Yang balance. Especially under conditions of obesity, adipose tissue secretes adipokines that contribute to establish a chronic inflammatory environment, promoting pathological processes such as atherosclerosis and insulin resistance. Skeletal muscles are capable of producing myokines that confer some of the health benefits of exercise. Such myokines might counteract the harmful effects of proinflammatory adipokines. Adapted, with permission, from ().



Figure 3.

Comparison of sepsis‐induced verses exercise‐induced increases in circulating cytokines. During sepsis, there is a marked and rapid increase in circulating tumor necrosis factor‐alpha (TNF‐α), which is followed by an increase in interleukin‐6 (IL‐6). In contrast, during exercise, the marked increase in IL‐6 is not preceded by elevated TNF‐α. Adapted, with permission, from ().



Figure 4.

Different modes of exercise and the corresponding increase in plasma interleukin‐6 (IL‐6) levels. Graph is based on 73 exercise trials and represents ∼800 subjects. Each dot indicates one exercise trial; the corresponding bars represent geometric means with 95% confidence intervals. Although different modes of exercise are associated with different levels of muscle damage, the increase in plasma IL‐6 levels postexercise is a consistent finding. Modified, with permission, from ().



Figure 5.

The overall log10‐log10 linear relation (straight solid line) between exercise duration and increase in plasma interleukin‐6 (IL‐6) (fold change from preexercise level) indicates that 51% of the variation in fold plasma IL‐6 increase may be explained by the duration of exercise. Modified, with permission, from ().



Figure 6.

The figure presents a model on how interleukin‐6 (IL‐6) is regulated in response to training adaptation. Regular exercise leads to an enhancement of glycogen synthase and a trained muscle will consequently store more muscle glycogen. During acute exercise, the untrained muscle is highly dependent on glycogen as substrate, whereas training leads to an enhancement of beta‐oxidating enzymes and an enhanced capability to oxidize fat and hence to use fat as substrate during exercise. This means that the trained muscle uses less glycogen during work. The activation of muscle‐IL‐6 is glycogen dependent. At conditions with low muscle glycogen, the transcription rate of IL‐6 is faster and relatively more IL‐6 is produced at the same relative work compared to conditions with high muscle glycogen. Thus, the acute plasma IL‐6 response is lower in a trained versus an untrained subject. The mechanisms whereby basal plasma‐IL‐6 is decreased by training and whereby the muscular expression of IL‐6 receptors (IL‐6R) is enhanced are not fully understood. However, it appears that a trained muscle may be more sensitive to IL‐6. Adapted, with permission, from ().



Figure 7.

Biological role of contraction‐induced interleukin‐6 (IL‐6). Skeletal muscle expresses and releases myokines into the circulation. In response to muscle contractions, both type I and type II muscle fibers express the myokine IL‐6, which subsequently exerts its effects both locally within the muscle (e.g., through activation of AMPK) and—when released into the circulation—peripherally in several organs in a hormone‐like fashion. Specifically in skeletal muscle, IL‐6 acts in an autocrine or paracrine manner to signal through a gp130Rβ/IL‐6Rα homodimer resulting in activation of AMP‐kinase and/or PI3‐kinase to increase glucose uptake and fat oxidation. IL‐6 is also known to increase hepatic glucose production during exercise or lipolysis in adipose tissue. Modified, with permission, from ().



Figure 8.

Exercise increases the intramuscular expression of peroxisome proliferator activated receptor γ coactivator 1α (PGC‐1α). Boström and colleagues recently reported that PGC‐1α, a transcriptional coactivator, stimulates the expression of the membrane protein fibronectin type III domain containing 5 (FNDC5), which is proteolytically cleaved to form irisin, a myokine. Irisin drives the transformation of white fat cells into brite cells—white fat cells with a phenotype similar to that of brown fat cells, as indicated by a marked increase in the expression of uncoupling protein 1 (UCP1) in white adipose tissue. The investigators also showed that an elevated level of plasma irisin, achieved through gene replacement, is followed by a reduction in body weight and an improvement in metabolic homeostasis in obese mice. Adapted, with permission, from ().



Figure 9.

Type 2 diabetes, cardiovascular diseases, colon cancer, postmenopausal breast cancer, dementia, and depression constitute a cluster of diseases, which can be identified as “the diseasome of physical inactivity”. Adapted, with permission, from ().



Figure 10.

Hypothesis: physical inactivity leads to accumulation of visceral fat and consequently to the activation of a network of inflammatory pathways, which promotes development of insulin resistance, atherosclerosis, neurodegeneration, and tumor growth, leading to the development of “the diseasome of physical inactivity.” Adapted, with permission, from ().



Figure 11.

MR‐scanning demonstrating visceral fat mass before and after 14 days of reduced daily stepping as described in ().



Figure 12.

The proposed cytokine signaling pathways for macrophages and contracting skeletal muscle. While it is well known that transcription of interleukin‐6 (IL‐6) and other proinflammatory cytokines such as tumor necrosis factor‐alpha (TNF‐α) and IL‐β is principally regulated by the Toll like receptor (##TLR) receptor signaling cascade that results in nuclear translocation and activation of NFκB, evidence in contracting skeletal muscle suggests that contraction leads to increased cytosolic Ca2+ and activation of p38 MAPK and/or calcineurin, which leads to activation of transcription factors depending upon these upstream events. Adapted, with permission, from ().



Figure 13.

The finding that muscle produces and releases myokines provides a conceptual basis for understanding some of the molecular mechanisms that link physical activity to protection against premature mortality ().

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Bente K. Pedersen. Muscle as a Secretory Organ. Compr Physiol 2013, 3: 1337-1362. doi: 10.1002/cphy.c120033